tbuckley/cabot-search huggingface dataset:
Prognostic value of plasma circulating tumor DNA fraction across four common cancer types: a real-world outcomes study
Authors: Z.R. Reichert, T.M. Morgan, G. Li, E. Castellanos, T. Snow, F.G. Dall’Olio, R.W. Madison, A.D. Fine, G.R. Oxnard, R.P. Graf, D.G. Stover
Journal: Annals of Oncology (2022)

Genomic analysis of circulating tumor DNA (ctDNA) is increasingly incorporated into the clinical management of patients with advanced cancer. Beyond tumor profiling, ctDNA analysis also can enable calculation of circulating tumor fraction (TF), which has previously been found to be prognostic. While most prognostic models in metastatic cancer are tumor type specific and require significant patient-level data, quantification of TF in ctDNA has the potential to serve as a pragmatic, tumor-agnostic prognostic tool.This study utilized a cohort of patients in a nationwide de-identified clinico-genomic database with metastatic castration-resistant prostate cancer (mCRPC), metastatic breast cancer (mBC), advanced non-small-cell lung cancer (aNSCLC), or metastatic colorectal cancer (mCRC) undergoing liquid biopsy testing as part of routine care. TF was calculated based on single-nucleotide polymorphism aneuploidy across the genome. Clinical, disease, laboratory, and treatment data were captured from the electronic health record. Overall survival (OS) was evaluated by TF level while controlling for relevant covariables.A total of 1725 patients were included: 198 mCRPC, 402 mBC, 902 aNSCLC, and 223 mCRC. TF ≥10% was highly correlated with OS in univariable analyses for all cancer types: mCRPC [hazard ratio (HR) 3.3, 95% confidence interval (CI) 2.04-5.34, P < 0.001], mBC (HR 2.4, 95% CI 1.71-3.37, P < 0.001), aNSCLC (HR 1.68, 95% CI 1.34-2.1, P < 0.001), and mCRC (HR 2.11, 95% CI 1.39-3.2, P < 0.001). Multivariable assessments of TF had similar point estimates and CIs, suggesting a consistent and independent association with survival. Exploratory analysis showed that TF remained consistently prognostic across a wide range of cutpoints.Plasma ctDNA TF is a pragmatic, independent prognostic biomarker across four advanced cancers with potential to guide clinical conversations around expected treatment outcomes. With further prospective validation, ctDNA TF could be incorporated into care paradigms to enable precision escalation and de-escalation of cancer therapy based on patient-level tumor biology.
Activation of Stimulator of IFN Genes (STING) Causes Proteinuria and Contributes to Glomerular Diseases
Authors: Alla Mitrofanova, Antonio Fontanella, Matthew Tolerico, Shamroop Mallela, Judith Molina David, Yiqin Zuo, Marcia Boulina, Jin-Ju Kim, Javier Santos, Mengyuan Ge, Alexis Sloan, Wadih Issa, Margaret Gurumani, Jeffrey Pressly, Marie Ito, Matthias Kretzler, Sean Eddy, Robert Nelson, Sandra Merscher, George Burke, Alessia Fornoni
Journal: Journal of the American Society of Nephrology (2022)

Significance Statement A signaling molecule that plays a role in the innate immune system, stimulator of IFN genes (STING), is a crucial regulator of the cyclic GMP-AMP synthase (cGAS)-STING pathway. This signaling pathway regulates inflammation and energy homeostasis under conditions of obesity, kidney fibrosis, and AKI, but its exact role in the pathogenesis of glomerular diseases remains unclear. The authors found that activation of STING in wild-type mice is sufficient to cause albuminuria and podocyte loss, and that the cGAS-STING signaling pathway is upregulated in mice with experimental diabetic kidney disease and Alport syndrome. They also demonstrated that either genetic or pharmacologic STING inhibition confers protection from kidney disease progression. These findings suggest that this signaling pathway plays an important role in mediating glomerular dysfunction. Background The signaling molecule stimulator of IFN genes (STING) was identified as a crucial regulator of the DNA-sensing cyclic GMP-AMP synthase (cGAS)-STING pathway, and this signaling pathway regulates inflammation and energy homeostasis under conditions of obesity, kidney fibrosis, and AKI. However, the role of STING in causing CKD, including diabetic kidney disease (DKD) and Alport syndrome, is unknown. Methods To investigate whether STING activation contributes to the development and progression of glomerular diseases such as DKD and Alport syndrome, immortalized human and murine podocytes were differentiated for 14 days and treated with a STING-specific agonist. We used diabetic db/db mice, mice with experimental Alport syndrome, C57BL/6 mice, and STING knockout mice to assess the role of the STING signaling pathway in kidney failure. Results In vitro , murine and human podocytes express all of the components of the cGAS-STING pathway. In vivo , activation of STING renders C57BL/6 mice susceptible to albuminuria and podocyte loss. STING is activated at baseline in mice with experimental DKD and Alport syndrome. STING activation occurs in the glomerular but not the tubulointerstitial compartment in association with autophagic podocyte death in Alport syndrome mice and with apoptotic podocyte death in DKD mouse models. Genetic or pharmacologic inhibition of STING protects from progression of kidney disease in mice with DKD and Alport syndrome and increases lifespan in Alport syndrome mice. Conclusion The activation of the STING pathway acts as a mediator of disease progression in DKD and Alport syndrome. Targeting STING may offer a therapeutic option to treat glomerular diseases of metabolic and nonmetabolic origin or prevent their development, progression, or both.
Characterization and corroboration of safety signals identified from the US Food and Drug Administration Adverse Event Reporting System, 2008-19: cross sectional study
Authors: Meera M Dhodapkar, Xiaoting Shi, Reshma Ramachandran, Evan M Chen, Joshua D Wallach, Joseph S Ross
Journal: BMJ (2022)

To characterize potential drug safety signals identified from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), from 2008 to 2019, to determine how often these signals resulted in regulatory action by the FDA and whether these actions were corroborated by published research findings or public assessments by the Sentinel Initiative.Cross sectional study.USA.Safety signals identified from the FAERS and publicly reported by the FDA between 2008 and 2019; and review of the relevant literature published before and after safety signals were reported in 2014-15. Literature searches were performed in November 2019, Sentinel Initiative assessments were searched in December 2021, and data analysis was finalized in December 2021.Safety signals and resulting regulatory actions; number and characteristics of published studies, including corroboration of regulatory action as evidenced by significant associations (or no associations) between the drug related to the signal and the adverse event.From 2008 to 2019, 603 potential safety signals identified from the FAERS were reported by the FDA (median 48 annually, interquartile range 41-61), of which 413 (68.5%) were resolved as of December 2021 (372 of 399 (93.2%) signals ≥3 years old were resolved). Among the resolved safety signals, 91 (22.0%) led to no regulatory action and 322 (78.0%) resulted in regulatory action, including 319 (77.2%) changes to drug labeling and 59 (14.3%) drug safety communications or other public communications from the FDA. For a subset of 82 potential safety signals reported in 2014-15, a literature search identified 1712 relevant publications; 1201 (70.2%) were case reports or case series. Among these 82 safety signals, 76 (92.7%) were resolved, of which relevant published research was identified for 57 (75.0%) signals and relevant Sentinel Initiative assessments for four (5.3%) signals. Regulatory actions by the FDA were corroborated by at least one relevant published research study for 17 of the 57 (29.8%) resolved safety signals; none of the relevant Sentinel Initiative assessments corroborated FDA regulatory action.Most potential safety signals identified from the FAERS led to regulatory action by the FDA. Only a third of regulatory actions were corroborated by published research, however, and none by public assessments from the Sentinel Initiative. These findings suggest that either the FDA is taking regulatory actions based on evidence not made publicly available or more comprehensive safety evaluations might be needed when potential safety signals are identified.
Maternal consumption of ultra-processed foods and subsequent risk of offspring overweight or obesity: results from three prospective cohort studies
Authors: Yiqing Wang, Kai Wang, Mengxi Du, Neha Khandpur, Sinara Laurini Rossato, Chun-Han Lo, Hannah VanEvery, Daniel Y Kim, Fang Fang Zhang, Jorge E Chavarro, Qi Sun, Curtis Huttenhower, Mingyang Song, Long H Nguyen, Andrew T Chan
Journal: BMJ (2022)

To assess whether maternal ultra-processed food intake during peripregnancy and during the child rearing period is associated with offspring risk of overweight or obesity during childhood and adolescence. Population based prospective cohort study. The Nurses' Health Study II (NHSII) and the Growing Up Today Study (GUTS I and II) in the United States. 19 958 mother-child (45% boys, aged 7-17 years at study enrollment) pairs with a median follow-up of 4 years (interquartile range 2-5 years) until age 18 or the onset of overweight or obesity, including a subsample of 2925 mother-child pairs with information on peripregnancy diet. Multivariable adjusted, log binomial models with generalized estimating equations and an exchangeable correlation structure were used to account for correlations between siblings and to estimate the relative risk of offspring overweight or obesity defined by the International Obesity Task Force. 2471 (12.4%) offspring developed overweight or obesity in the full analytic cohort. After adjusting for established maternal risk factors and offspring's ultra-processed food intake, physical activity, and sedentary time, maternal consumption of ultra-processed foods during the child rearing period was associated with overweight or obesity in offspring, with a 26% higher risk in the group with the highest maternal ultra-processed food consumption (group 5) versus the lowest consumption group (group 1; relative risk 1.26, 95% confidence interval 1.08 to 1.47, P for trend<0.001). In the subsample with information on peripregnancy diet, while rates were higher, peripregnancy ultra-processed food intake was not significantly associated with an increased risk of offspring overweight or obesity (n=845 (28.9%); group 5 v group 1: relative risk 1.17, 95% confidence interval 0.89 to 1.53, P fortrend=0.07). These associations were not modified by age, sex, birth weight, and gestational age of offspring or maternal body weight. Maternal consumption of ultra-processed food during the child rearing period was associated with an increased risk of overweight or obesity in offspring, independent of maternal and offspring lifestyle risk factors. Further study is needed to confirm these findings and to understand the underlying biological mechanisms and environmental determinants. These data support the importance of refining dietary recommendations and the development of programs to improve nutrition for women of reproductive age to promote offspring health.
AAV vectors: The Rubik’s cube of human gene therapy
Authors: Amaury Pupo, Audry Fernández, Siew Hui Low, Achille François, Lester Suárez-Amarán, Richard Jude Samulski
Journal: Molecular Therapy (2022)

Defective genes account for ∼80% of the total of more than 7,000 diseases known to date. Gene therapy brings the promise of a one-time treatment option that will fix the errors in patient genetic coding. Recombinant viruses are highly efficient vehicles for in vivo gene delivery. Adeno-associated virus (AAV) vectors offer unique advantages, such as tissue tropism, specificity in transduction, eliciting of a relatively low immune responses, no incorporation into the host chromosome, and long-lasting delivered gene expression, making them the most popular viral gene delivery system in clinical trials, with three AAV-based gene therapy drugs already approved by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA). Despite the success of AAV vectors, their usage in particular scenarios is still limited due to remaining challenges, such as poor transduction efficiency in certain tissues, low organ specificity, pre-existing humoral immunity to AAV capsids, and vector dose-dependent toxicity in patients. In the present review, we address the different approaches to improve AAV vectors for gene therapy with a focus on AAV capsid selection and engineering, strategies to overcome anti-AAV immune response, and vector genome design, ending with a glimpse at vector production methods and the current state of recombinant AAV (rAAV) at the clinical level. Defective genes account for ∼80% of the total of more than 7,000 diseases known to date. Gene therapy brings the promise of a one-time treatment option that will fix the errors in patient genetic coding. Recombinant viruses are highly efficient vehicles for in vivo gene delivery. Adeno-associated virus (AAV) vectors offer unique advantages, such as tissue tropism, specificity in transduction, eliciting of a relatively low immune responses, no incorporation into the host chromosome, and long-lasting delivered gene expression, making them the most popular viral gene delivery system in clinical trials, with three AAV-based gene therapy drugs already approved by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA). Despite the success of AAV vectors, their usage in particular scenarios is still limited due to remaining challenges, such as poor transduction efficiency in certain tissues, low organ specificity, pre-existing humoral immunity to AAV capsids, and vector dose-dependent toxicity in patients. In the present review, we address the different approaches to improve AAV vectors for gene therapy with a focus on AAV capsid selection and engineering, strategies to overcome anti-AAV immune response, and vector genome design, ending with a glimpse at vector production methods and the current state of recombinant AAV (rAAV) at the clinical level.
A protein encoded by circular ZNF609 RNA induces acute kidney injury by activating the AKT/mTOR-autophagy pathway
Authors: Xin Ouyang, Zhimei He, Heng Fang, Huidan Zhang, Qi Yin, Linhui Hu, Fei Gao, Hao Yin, Taofang Hao, Yating Hou, Qingrui Wu, Jia Deng, Jing Xu, Yirong Wang, Chunbo Chen
Journal: Molecular Therapy (2022)

(Molecular Therapy 31; January 2023) In the originally published version of this article, a hyphen was omitted in the title due to a production error. The correct title is “A protein encoded by circular ZNF609 RNA induces acute kidney injury by activating the AKT/mTOR-autophagy pathway.” Cell Press apologizes for this error, and this has been corrected online. A protein encoded by circular ZNF609 RNA induces acute kidney injury by activating the AKT/mTOR-autophagy pathwayOuyang et al.Molecular TherapySeptember 14, 2022In BriefAutophagy regulated by circRNAs is of concern in ischemic acute kidney injury (AKI). Herein, we find that highly expressed circ-ZNF609-encoded ZNF609-250aa induces cell apoptosis and AKI by impairing autophagy flux via the AKT/mTOR signaling pathway. These findings imply that targeting circ-ZNF609 may be a novel therapy for ischemic AKI. Full-Text PDF
Choroid plexus-derived extracellular vesicles exhibit brain targeting characteristics
Authors: Marie J. Pauwels, Junhua Xie, Adam Ceroi, Sriram Balusu, Jonas Castelein, Elien Van Wonterghem, Griet Van Imschoot, Andrew Ward, Trevelyan R. Menheniott, Oskar Gustafsson, Francis Combes, Samir EL Andaloussi, Niek N. Sanders, Imre Mäger, Lien Van Hoecke, Roosmarijn E. Vandenbroucke
Journal: Biomaterials (2022)
Characterizing the biology of primary brain tumors and their microenvironment via single-cell profiling methods
Authors: L Nicolas Gonzalez Castro, Ilon Liu, Mariella Filbin
Journal: Neuro-Oncology (2022)

Genomic and transcriptional heterogeneity is prevalent among the most common and aggressive primary brain tumors in children and adults. Over the past 20 years, advances in bioengineering, biochemistry and bioinformatics have enabled the development of an array of techniques to study tumor biology at single-cell resolution. The application of these techniques to study primary brain tumors has helped advance our understanding of their intra-tumoral heterogeneity and uncover new insights regarding their co-option of developmental programs and signaling from their microenvironment to promote tumor proliferation and invasion. These insights are currently being harnessed to develop new therapeutic approaches. Here we provide an overview of current single-cell techniques and discuss relevant biology and therapeutic insights uncovered by their application to primary brain tumors in children and adults.
Will Exercise Help Keep Women Away From Oncologists—or Obstetricians?
Authors: Marsha F. Goldsmith
Journal: JAMA (1988)

DELAYING MENARCHE in American adolescents might bring about unsuspected societal, as well as personal, benefits if the conclusions of some recent widely reported studies on exercise and women's health are accepted. On the other hand, it might be best not to try to fool Mother Nature. Speaking in Boston at the annual meeting of the American Association for the Advancement of Science (AAAS), Rose E. Frisch, PhD, associate professor in the Department of Population Sciences at the Harvard School of Public Health, Boston, presented some provocative data that seem to suggest reasons for seriously slimming the average teenage girl's figure while also temporarily repressing her libido. But another speaker at a symposium on "Effects of Intensive Exercise on Female and Male Reproduction" weighed in in favor of the status quo. David C. Cumming, MB, associate professor, Department of Obstetrics and Gynecology and Medicine (Division of Endocrinology), University of Alberta Faculty
Kirke's Handbook of Physiology.
Journal: JAMA (1923)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Dermatitis herpetiformis and bullous pemphigoid: a developing association confirmed by immunoelectronmicroscopy
Authors: J. SETTERFIELD, B. BHOGAL, M.M. BLACK, D.H. MCGIBBON
Journal: British Journal of Dermatology (1997)

Summary We report a case of dermatitis herpetiformis associated with bullous pemphigoid in which the clinical, histopathological and immunopathological findings were corroborated by direct immunoelectronmicroscopy performed on normal and peri–lesional skin biopsies. Western immunoblotting detected the 180kDa BPAG2 consistent with bullous pemphigoid. HLA–typing confirmed the DR3 DQ2 haplotype associated with dermatitis herpetiformis.
THE INTERNATIONAL CONGRESS OF ARTS AND SCIENCE.
Journal: JAMA (2004)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Physiology and Biochemistry in Modern Medicine.
Journal: JAMA (1920)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Restless Legs and Nocturnal Myoclonus
Authors: David M. Bee
Journal: JAMA (1985)

<h3>To the Editor.—</h3> I am responding to the comment by Dr Dyck<sup>1</sup>regarding restless leg syndrome. I am puzzled that Dr Dyck's response does not mention nocturnal myoclonus, a well-described neurological disorder that is associated with restless legs. Nocturnal myoclonus is a surprisingly common phenomenon, the diagnosis of which is not difficult and the treatment for which is very satisfactory. Benzodiazepines such as alprazolam or clonazepam are generally highly effective for this disorder in modest doses, and alprazolam is, at least, remarkably safe.